Autism Spectrum Disorders

Suzannah Cox, PharmDPediatric Pharmacy ResidentErnest Mario School of Pharmacy atRutgers, the State University of New JerseyPiscataway, New Jersey

Anita Siu, PharmDClinical Associate ProfessorClinical Neonatal/Pediatric Pharmacotherapy SpecialistErnest Mario School of Pharmacy atRutgers, the State University of New JerseyPiscataway, New Jersey

US Pharm. 2012;37(3):37-42.

Autism spectrum disorders (ASDs) are a group of
developmental disabilities in which patients have delayed development in
skills associated with socialization, communication, and overall
behavior. The broader term of ASD includes Pervasive Developmental
Disorder-Not Otherwise Specified (PDD-NOS), Asperger’s Disorder, and
Autistic Disorder (AD). Currently all three of these disorders have
their own separate diagnostic criteria. Patients with PDD-NOS will meet
some, but not all, of the diagnostic criteria for AD and will generally
have milder symptoms compared to AD patients.1 Patients with
Asperger’s Disorder have unusual interests and behaviors and social
challenges, but do not have intellectual deficits.1 Patients
with AD, however, have both social as well as intellectual impairments.
According to the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR), the diagnosis of AD requires1:

Despite these structured characteristics needed for
diagnosis, patients can have a wide variety of symptoms. They can be
highly functioning students who successfully complete a college degree
and possess mildly inadequate social skills, or they can be nonverbal
individuals with severe mental retardation.2TABLE 1 lists the DSM-IV-TR diagnostic criteria for AD.1

The prevalence of patients with ASDs has risen over the
past few decades. As of 2006, it has been estimated that an average of
one in 110 children in the United States has an ASD, with approximately
730,000 individuals under 21 years of age diagnosed with an ASD.3
Instead of being a true increase in the number of patients with ASDs,
this rise could be due to policy and practice changes, which improves
awareness on the spectrum of the disorders and diagnoses of ASDs.4

The DSM-V is scheduled to be released in 2013. One of the
major revisions includes the diagnostic criteria for AD. Under the
proposed revisions, the three diagnoses of AD, Asperger’s Disorder, and
PDD-NOS will be consolidated under one category of ASD. Several experts
are concerned that this may potentially diagnose fewer patients with AD
because of more stringent diagnostic criteria. Physicians involved in
the DSM taskforce who are proposing the revisions state that the new
diagnostic tool will provide clarity and not decrease the number of
patients being diagnosed. The process will be carefully monitored.5

Risk Factors And Pathophysiology

Over the past several decades, there has been a
considerable amount of research to determine the risk factors and
underlying pathophysiology of ASDs, including AD. While still somewhat
controversial, current evidence supports a major genetic component and
environmental factors playing an important role in the etiology of
autism.6

Genetic Links:The ratio of males to females diagnosed with AD is approximately three to one.2
Since the diagnosis is more common in males, this has led to discussion
that AD could be an X-linked disorder. Data to support this hypothesis
are inconsistent with cases of male-to-male transmission of AD within
families, which would argue against this theory.2 But it is
also known that when assessing patients with AD who have other comorbid
genetic diseases, one of the more frequently shared diseases is Fragile X
Syndrome (FXS). It is an X-linked disorder and the most common cause
for inherited intellectual disability.7 Just like those with
AD, patients with FXS include a wide spectrum of symptoms, with the most
consistent one being developmental delay. Approximately 30% of patients
with FXS are on the autism spectrum; however, this population still
only comprises a small percentage of patients who are diagnosed with an
ASD.2

Further potential genetic links have been identified when
looking at the association of AD between siblings. The rate of
recurrence is 2% to 8% among children with siblings who have been
diagnosed with AD. When comparing monozygotic to dizygotic twins, there
is a concordance of greater than 60% in monozygotic twins, with almost
no concordance in dizygotic twins.8,9
However, the fact that the concordance is not 100% suggests that there
may be some aspect of environmental influence to the disorder.2

Environmental Factors:Similar to the
ambiguity of the genetic links discussed above, there are no definitive
environmental factors known to be linked to the development of an ASD.
Studies since 1979 have investigated the link of ASD with environmental
factors showing inconclusive results. Potential risk factors in the
studies that were identified include advanced maternal age, low birth
weight, breech presentation, and respiratory distress syndrome, but no
single factor was consistently recognized in all of the studies.10-17

A recent study conducted out of Atlanta, Georgia, focused
on estimating the birth weight- and gestational age-specific risks of
autism.18 The authors found that when compared to control
patients who were not receiving special education services, there was a
2.3-fold increased risk of autism in children who were born weighing
<2.5 kg. Furthermore, after stratifying according to gestational age,
the risk of autism in preterm infants (<37 weeks’ gestation)
weighing <2 kg was elevated compared to control patients, but was not
statistically significant.18

Another study from Utah looked more generally at the
prenatal, perinatal, and neonatal risk factors associated with the
development of an ASD.19 By using a population-based, nested
case-control design, they were able to find a statistically significant
association between increased maternal age (>35 years old) and a risk
of ASDs. They also found a significant link between the risk for ASDs
and the baby being in the breeched position prior to birth. However,
when analyzing neonatal risk factors such as birth weight, 5-minute
Apgar scores (a scoring system used to rapidly assess the status of a
newborn),20 congenital anomalies, and assisted ventilation
for greater than 30 minutes, they did not find an association with an
increased risk of AD.19

Despite the results of these trials, there is still no consensus on what risk factors truly have a link to the development of an ASD.

Vaccines:In addition to the
potential risk factors stated above, more commonly discussed is the link
between vaccines and ASDs. Of significant concern were vaccines that
included a mercury-containing compound called thimerosal that was added in order to protect multiple-dose vials from bacterial contamination.21
Although there was no evidence that the low doses of thimerosal in
vaccines caused harm in pediatrics, in 1999 the American Academy of
Pediatrics (AAP) and the Public Health Service agencies, along with the
vaccine manufacturers, agreed to eliminate or reduce the content of
thimerosal in vaccines as a precautionary measure.22

In 2010, Lewis et al compared children ages 6 to 13
receiving mercury exposure from thimerosal-containing products,
including vaccines, with any of the three ASD outcomes, including ASD,
AD, and ASD with regression.23 The study included a total of
256 case-children and 752 matched controls and found no evidence that
there was an increased risk of ASD, AD, or ASD with regression. To
further support the argument that thimerosal does not contribute to the
development of an ASD, it is now known that the rate of diagnosis of
ASDs has continued to climb despite the removal of thimerosal from
vaccines more than a decade ago.24

More specifically, the measles, mumps, and rubella (MMR)
vaccine has been most commonly selected as having a link with increasing
rates of autism. In 1998, Wakefield et al published an article in The Lancet that suggested a link between the MMR vaccine and autism.25
However, in 2004, 10 out of the original 12 authors printed a
retraction that acknowledged that there was insufficient evidence to
establish the previously stated causal link,26 and in 2010
the editors of the journal officially published a retraction of the
original article, again emphasizing that several elements presented in
the article were incorrect.27

In 2002, Madsen et al published the results of their
retrospective cohort study that was designed to evaluate the
relationship between autism and the MMR vaccine in a population of
children who were born in Denmark.28 A total of 537,303
children were included in the cohort. Eighty-two percent of the included
patients were vaccinated with the MMR vaccine and a total of 316
children were diagnosed with AD, with an additional 422 children being
diagnosed with other ASDs. After adjusting for age, calendar period,
sex, birth weight, gestational age, mother’s education, and
socioeconomic status, they found that when compared to unvaccinated
children, there was no increase in the risk of AD or other ASDs among
those children who were vaccinated.28

Goals of Treatment

Goals of therapy focus on maximizing the patient’s independence and quality of life and alleviating family stress.29
Furthermore, core features of the disorder, including deficits in
communication and social skills, are minimized. The education and
support provided to families, in addition to facilitating learning and
development of the patient, can help accomplish these goals.

Nonpharmacologic Treatment Options

Due to the incurable nature of AD, effective chronic management options are essential to effective treatment of the disorder.29
Currently, the cornerstone of therapy focuses on nonpharmacologic
treatments, including behavioral therapy, with the addition of
pharmacologic agents if needed. Due to the importance of early
intervention in this patient population, the Education of All
Handicapped Children Act of 1975 made the education of patients with AD a
public responsibility.30 The National Research Council
formed the Committee on Educational Interventions for Children with
Autism in order to evaluate the current literature regarding treatment
options and provide appropriate recommendations for public policy.31

While there are several different methodologies on
effective behavioral therapy for patients with AD currently available,
two of the primary resources are Applied Behavior Analysis (ABA) and the
Treatment and Education of Autistic and Related Communication
Handicapped Children (TEACCH) program. ABA uses psychological
conditioning to systematically teach skills associated with social,
communication, and behavioral management. It utilizes positive
reinforcement to teach new behaviors, and addresses destructive behavior
that can be harmful to the patient as well as others by analyzing the
underlying factors to make an effective behavioral modification.21,29,32
ABA also longitudinally evaluates the effectiveness of the therapy so
that the interventions can be modified according to the progress being
made. Ideally, treatment is started as soon as possible after diagnosis
and requires 20 hours of intervention per week for patients to achieve
the maximum results.21

On the other hand, the TEACCH program focuses on a
specific strength of patients with AD. For example, the processing of
visual information is emphasized in contrast to verbal communication,
which is more likely to be lacking in this patient population.21,32
The program utilizes controlled and organized classrooms that have
structured learning activities that are broken down into visually
organized steps.

One of the landmark studies carried out regarding behavioral therapy for patients with AD was conducted by Lovaas in 1987.33
The study looked at the results of behavioral modification treatment
for two groups of similar preschool-aged children. Of the 19 children
who were treated with intensive behavioral therapy, 47% achieved normal
intellectual and educational functioning compared to the control group
of 40 children, where only 2% achieved the same result.33

A follow-up study was conducted in 1993 by McEachin et al following the same 19 patients at a mean age of 11.5 years.34
Their study showed that the intensive behavioral therapy group retained
its gains over the control group, signifying that behavioral treatment
can produce long-lasting improvements for many children who have AD.34

While younger children are usually the focus of targeted
behavioral therapy, it is important to keep in mind that as these
patients grow into adolescence and adulthood, they will generally need
continual support. Patients with AD may need assistance in finding
meaningful employment, and they often have the opportunity to live in
group homes when their families can no longer provide support or
shelter.35 If the network of support is continued, it will
help decrease the number of patients with AD requiring long-term
facilities in the future.

Pharmacologic Treatment Options

The use of pharmacologic agents in patients who have ASDs
generally focuses on alleviating certain behavioral symptoms such as
irritability, hyperactivity, aggression, and other self-injurious
behaviors that can be detrimental to the child’s ability to learn, as
well as to their family environment. The percentage of patients with AD
who exhibit aggressive behaviors has not yet been evaluated; however,
one study found that approximately 20% of patients with PDD experience
moderate-to-severe irritability.36 Currently, there are only
two FDA-approved medications for treating irritability associated with
autism. These drugs, risperidone and aripiprazole, are both classified
as atypical antipsychotics, which work by blocking postsynaptic dopamine
and serotonin receptors. TABLE 2 provides a summary of the dosing and adverse effects for both agents.37,38

Risperidone:This drug was approved
in October 2006 by the FDA for the treatment of irritability associated
with autism in children and adolescents 5 to 16 years of age.37
Risperidone, an atypical antipsychotic, antagonizes both serotonin as
well as dopaminergic receptors, with a greater affinity for the
serotonin receptors. The decision to approve risperidone for the
treatment of autism came after the publication of a few key studies. One
of the main trials included an 8-week randomized treatment period
followed by a 4-month open-label treatment and a 2-month discontinuation
phase.39 The study was designed to look for a decrease in
the Aberrant Behavior Checklist (ABC) irritability subscale score that
asked questions related to aggression, self-injury, tantrums,
agitations, and unstable mood. The first treatment period included 101
children 5 to 17 years old who were randomized to receive either placebo
or risperidone. Risperidone was initiated at a dose of 0.25 mg at
bedtime for patients that weighed <20 kg and 0.5 mg for patients who
weighed ≥20 kg. The dose could be titrated appropriately until day 29 of
the study. The results showed a 56.9% decrease in the mean irritability
score for patients receiving risperidone compared to a 14.1% decrease
in the placebo group, a difference which was statistically significant (P
<.001). Adverse events reported were mostly mild, and included
increased appetite, nasal congestion, fatigue, vomiting, weight gain,
drooling, constipation, and xerostomia.39 While not seen in this study, QT prolongation can also be a concern when prescribing risperidone to patients.37

The extension trial was an open-label study and included
63 patients who showed a positive response to risperidone or who were
nonresponders to placebo.40 Treatment with risperidone was
continued for an additional 4 months, after which 38 patients enrolled
in the 2-month discontinuation phase, where they were randomized to
either continue treatment with risperidone or be transitioned over to
placebo. Results from the 4-month treatment period continued to show a
significant improvement in symptoms for 80% of patients, with continued
tolerability as well. The discontinuation phase demonstrated that as
patients came off the risperidone, they started to show a return of
aggressive behavior, signifying that continuation of medication can help
maintain the control of symptoms. While this was an extension trial,
patients were still only treated for a maximum of 8 months, so long-term
efficacy and tolerability are unknown.40 Additional trials
involving risperidone have also shown promising data in patients who
suffer from aggressive behavior associated with ASDs.41,42

Aripiprazole:In November 2009, after
two randomized controlled trials, the FDA approved aripiprazole for the
treatment of irritability associated with ASDs in patients 6 to 17
years of age.38 Aripiprazole is also an atypical
antipsychotic that is a functional antagonist of specific serotonin
receptors. In addition, it has partial agonist activity at other
serotonin and dopaminergic receptors. Similar to risperidone, these
randomized, placebo-controlled trials were designed to measure the mean
change from baseline to endpoint in the caregiver-rated ABC irritability
subscale score.

The first trial was a fixed-dose study that included 218
patients, aged 6 to 17 years, who were randomized to receive either
placebo or aripiprazole 5, 10, or 15 mg/day for the total treatment
duration of 8 weeks.43 The results of this study showed that
for the primary outcome, patients who received placebo had a mean
decrease on the irritability subscale score of 8.4 compared to a
decrease of 12.4 for patients who received aripiprazole 5 mg/day, 13.2
for patients who received 10 mg/day, and 14.4 for patients who received
15 mg/day. All of these values were statistically significant (P
<.05). Eighty-four percent of patients reported one adverse event
during the study; however, most of them were considered mild to moderate
and included sedation, fatigue, increased appetite, headache,
extrapyramidal symptoms, and weight gain.43 While this
short-term study showed the benefit of aripiprazole in this unique
patient population, the long-term effects, favorable and unfavorable,
are still widely unknown.

The second trial was a flexible-dose study that randomized
98 patients, aged 6 to 17 years, to receive either placebo or
aripiprazole for the total treatment duration of 8 weeks.44
For patients who received aripiprazole, their dose was initiated at 2
mg/day and was titrated to a target dose of 5, 10, or 15 mg/day, as
deemed appropriate by the investigator, making sure that the dose
remained stable for the final 2 weeks of treatment. Similar to the first
study, the results showed a statistically significant difference with a
mean decrease from baseline on the irritability subscale score of 12.9
for patients who received aripiprazole compared to 5 for patients who
received placebo. This study also demonstrated that a majority of
patients experienced at least one adverse event, generally mild in
nature and similar to those listed above. This trial had the advantage
of administering only 5 or 10 mg/day of aripiprazole to the majority of
patients during the last 2 weeks of treatment, suggesting that these
lower doses might be sufficient to achieve the desired results.44
Information regarding long-term efficacy and safety is still lacking;
however, aripiprazole does have a black box warning regarding the
increased risk of suicidal thinking and behavior in children,
adolescents, and young adults with major depressive disorder and other
psychiatric disorders.38

Off-label Use:Other medications have
also been studied for the treatment of repetitive and aggressive-type
behaviors in ASDs. These drugs include the selective serotonin reuptake
inhibitors (SSRIs) fluoxetine and fluvoxamine as well as atomoxetine, a
selective norepinephrine reuptake inhibitor (SNRI).29,45 Furthermore, the alpha2-adrenergic agonists guanfacine and clonidine have also been investigated for the treatment of patients with ASDs.29,45
While these drugs have shown promise in a limited number of trials, the
data are more restricted, and these agents are not FDA approved for
these indications in patients with ASDs.

Conclusion

While there are several theories concerning the main
causes of ASDs, the data remain somewhat controversial but support a
pathway that is most likely a combination of both genetic links and
environmental factors. Treatment for patients with ASDs should focus on
early intervention with behavioral modification therapy, with the
addition of pharmacologic agents if necessary to help manage
aggressive-type behaviors. Pharmacists can play a key role in educating
families on the different medications available and how to take them
appropriately, if prescribed.